Method for producing a 1-(3-cyclopentenyloxy-4-alkoxyphenyl)-4-oxocyclohexanecar-bonitrile

ABSTRACT

This invention relates to a process for converting isovanillin to substituted 4-cyano-4-(3,4-disubstitutedphenyl)cyclhexanones. These ketones are useful in preparing certain PDE4 ingibitors wherein the 1-postion keto group is converted to a carboxylic acid group.

This is a 371 of international Application PCT/EP98/05504, filed Aug.26, 1998.

The present invention concerns a new process for production of a1-(3-cyclopentyloxy-4-alkoxyphenyl)-4-oxocyclohexanecarbonitrilestarting from 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)heptanediaciddialkyl ester.

1-(3-cyclopentyloxy-4-alkoxyphenyl)-4-oxocyclohexanecarbonitrile,abbreviated CMC below, is used in the manufacture of pharmaceuticals,for example in the production of phenylcyclohexane-1-ylcarboxylic acidderivatives, which inhibit the production of tumor necrosis factor (WO95/24381).

There are several known processes for production of CMC. For example, WO95/24381 describes a 4-stage procedure for production of CMC that beginswith 3-cyclopentyloxy-4-methoxybenzaldehyde. In this procedure,3-cyclopentyloxy-4-methoxybenzaldehyde is converted into3-cyclopentyloxy-4-methoxyphenylacetonitrile, which with Triton-B andmethyl acrylate is turned into the4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)heptanediacid dimethylester. The latter, in the presence of a strong base, is then cyclizedinto5-cyano-5-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxocyclohexanecarboxylicacid methyl ester, which upon dissolution in dimethyl sulfoxide isdecarboxylated to form CMC. With this procedure, CMC is obtained througha quite involved process with several changes of solvent at a yield ofapproximately 60% relative to4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)heptanediacid dimethylester, which is abbreviated as CMD below. The two disadvantages of thisprocedure are the mediocre yield and the use of dimethyl sulfoxide(DMSO) in an environment in which the solvent is inclined to thermaldecomposition.

The goal of the present invention was to provide a simpler process forthe production of CMC in which the desired product is isolated with goodyields.

This goal is achieved with the process according to claim 1. Accordingto the invention, the process is carried out such that CMD, of thegeneral formula

wherein R¹, R² and R³ represent C₁₋₅-alkyl groups, is cyclized in thepresence of a base to a5-cyano-5-(3-cyclopentyloxy-4-alkoxyphenyl)-2-oxocyclohexanecarboxylicacid alkyl ester, abbreviated CMOM below, of the general formula

wherein R¹ and R² have the given meaning, the compound of the generalformula III is neutralized with an alkali metal hydrogen carbonate, andis then decarboxylated in the presence of an alkali metal carbonate toform the end product of formula I.

C₁₋₅-alkyl can be defined below as methyl, ethyl, propyl, isopropyl,butyl, tert-butyl and pentyl.

An alkali metal hydride or an alkoxide [1] may be used as base. Examplesof alkoxides that can be used include alkali metal alkoxides such assodium or potassium methoxide, sodium or potassium ethoxide, sodium orpotassium propoxide, or sodium or potassium butoxide. Sodium hydride,for example, may be used as the alkali metal hydride.

Sodium or potassium hydrogen carbonate may be used as the alkali metalhydrogen carbonate.

It is expedient to carry out the cyclization of the CMD to the CMOM at atemperature of 20 to 100° C., preferably from 50 to 70° C. Thedecarboxylation of the CMOM to the CMC is efficiently conducted at atemperature of 20 to 100° C., preferably from 70 to 90° C.

It is expedient to carry out the decarboxylation under weakly basicconditions, preferably between pH 8 and pH 12.

Polar solvents such as ether may be used as the solvent for thecyclization and decarboxylation. Dioxane, diethyl ether, dibutyl ether,anisole, tetrahydrofuran or mono-, di-, tri- or polyethyleneglycolether, such as 1,2-dimethoxyethane may be used as the ether.

The production of the educt, the CMD of general formula II, is known inprinciple from PCT WO 93/19 750. It is expedient to produce the CMD ofgeneral formula II such that in a first stage, an isovanillin derivativeof the general formula

wherein R¹ has the given meaning, is reacted with a halogen cyclopentaneto form a 3-cyclopentyloxy-4-methoxybenzaldehyde of the general formula

wherein R¹ has the given meaning.

It is expedient to conduct the conversion in the first stage in thepresence of an alkali metal or earth alkaline metal carbonate. Sodium orpotassium carbonate may be used as the alkali metal carbonate andmagnesium or calcium carbonate may be used as the earth alkaline metalcarbonate.

Fluoro-, chloro-, bromo- or iodocyclopentane may be used as the halogencyclopentane.

The conversion in the first stage is efficiently conducted in a polarsolvent. Examples of polar solvents that may be used includedimethylformamide (DMF) or a C₁₋₄-alcohol such as methanol, ethanol,propanol or butanol. Methanol is preferable.

The conversion in the first stage is effectively conducted at atemperature of 100 to 130° C., preferably 110 to 125° C.

In the second stage, the 3-cyclopentyloxy-4-methoxybenzaldehyde isreduced to the (3-cyclopentyloxy-4-methoxyphenyl)methanol of the generalformula

The reduction is efficiently conducted with sodium or potassiumborohydride.

It is expedient to carry out the reduction in the second stage at atemperature of −10 to 90° C., preferably 0 to 25° C.

The reduction is usually conducted in an atmosphere of inert gas. Thesame solvents used in the first stage may be used here.

In the third stage, the (3-cyclopentyloxy-4-methoxyphenyl)methanol ishalogenated to a 4-(halogenmethyl-2-cyclopentyloxy-1-alkoxy)benzene ofthe formula

Hydrogen chloride or bromide, especially an aqueous solution of hydrogenchloride or bromide, may be used as the halogenation agent. Hydrogenchloride is preferable.

It is expedient to conduct the halogenation in an atmosphere of inertgas in a hydrocarbon solvent. Toluene, xylol or benzene may be used asthe hydrocarbon.

It is expedient to conduct the halogenation at a temperature of 0 to 50°C., preferably 10 to 25° C.

In the fourth stage, the(halogenmethyl-2-cyclopentyloxy-1-alkoxy)benzene is converted into a(3-cyclopentyloxy-4-alkoxyphenyl)acetonitrile of the general formula

wherein R¹ has the given meaning.

The conversion in the fourth stage is effectively conducted in anatmosphere of inert gas and in a polar solvent. The same solvents usedin the first and the second stages may be used as the polar solvent.

The fourth stage is usually carried out with an alkali metal cyanidesuch as sodium or potassium cyanide.

The conversion in the forth stage is effectively carried out at atemperature of 10 to 100° C., preferably 20 to 50° C.

In the fifth stage, the (3-cyclopentyloxy-4-alkoxyphenyl)acetonitrile iscombined with an alkyl acrylate to form the CMD of the general formula

Methyl, ethyl, propyl or butyl acrylate may be used as the alkylacrylate.

The conversion in the fifth stage is effectively carried out in thepresence of a base, as for example in the presence of a non-ionictenside such as Triton B.

The conversion in the fifth stage may be conducted in a polar solvent.Acetonitrile and DMF are suitable polar solvents.

The conversion in the fifth stage is effectively conducted at atemperature of 0 to 60° C., preferably 20 to 40° C.

The inventive process for production of CMC of the general formula I issimple to carry out due to the few required solvent changes and deliversthe desired product at a yield of 70 to 80%.

EXAMPLE 1 Production of (3-cyclopentyloxy-4-methoxyphenyl)methanol

800 g DMF, 140 g (0.916 mol) isovanillin, 254 g (1.831 mol) potassiumcarbonate and 193 g (1.825 mol) chlorocyclopentane were combined andheated to 120-125° C. After 3 h, the mixture was cooled to 25° C.,filtered and washed with 508 g methanol. The filtrate was cooled to 0-5°C. and mixed in 4 portions within 1 h at 0-15° C. with 10.8 g sodiumborohydride. Thirty minutes after this mixing ended, the mixture waswarmed to 25-30° C. and stirred at this temperature for 2 h. The mixturewas then cooled to 10-15° C. and 63 g hydrochloric acid (19.5%) wasadded to it over 20 minutes. Then the majority of the solvent wasdistilled off under vacuum. One then added 1,160 g water and 1,036 gtoluene to the residue, stirred for 5 min and removed the lower waterphase. The extraction was repeated twice with a total of 995 g E-water¹.1,230.9 g organic phase were obtained (assay 15.61 weight-%(3-cyclopentyloxy-4-methoxyphenyl)methanol, GC with internal standard).Yield: 94.4% relative to isovanillin

EXAMPLE 2

Production of (4-chloromethyl-2-cyclopentyloxy-1-methoxy)benzene

327.8 g (3-cyclopentyloxy-4-methoxyphenyl)methanol solution in toluene(produced from 0.356 mol isovanillin) were put into a flask made inertwith N₂ at 21.5° C. Over 1 hour, 105.5 g 32% HCl (0.926 mol) was addedby drops so that the temperature remained below 25° C. The reactionmixture was diluted with 110 g toluene and the phases were separated.The organic phase was mixed with 10 g solid NaHCO₃, stirred for 10 minand filtered. The filtrate was concentrated. 94.1 g(4-chloromethyl-2-cyclopentyloxy-1-methoxy)benzene was obtained in crudeform as a brown oil.

EXAMPLE 3 Production of (3-cyclopentyloxy-3-methoxyphenyl)acetonitrile

85.16 g of crude (4-chloromethyl-2-cyclopentyloxy-1-methoxy)benzene(produced from 0.364 mol isovanillin) and 230 g DMF were put into aflask made inert with N₂ at 21° C. 10.7 g NaCN were added to the clearsolution. The temperature rose to 28.5° C. within 1 hour. Then another10.7 g NaCN were added. The reaction mixture was stirred for anotherhour and then heated to 50° C. over 30 min. After stirring for another1.5 h at 50° C., the solvent was distilled off as completely aspossible. The residue was extracted with 365 g toluene and 125 g water.The organic phase was concentrated under vacuum. 78.5 g of crude(3-cyclopentyloxy-3-methoxyphenyl)acetonitrile were obtained in the formof brown oil (assay by GC with internal standard: 89.3%). Yield: 83.3%relative to isovanillin.

EXAMPLE 4 Production of CMD

82.2 g of crude (3-cyclopentyloxy-3-methoxyphenyl)acetonitrile (assay:89.0%, 0.316 mol), 406 g acetonitrile and 1 g water were put into aflask made inert with N₂ at 21° C. A solution of 94 g methyl acrylate(1.092 mol) in 54.5 g acetonitrile was prepared in a dropping funnel; asolution of 12.72 g 35% methanolic benzyltrimethyl ammonium hydroxidesolution (Triton-B) (containing approximately 5% water) in 54.5 gacetonitrile was prepared in another dropping funnel. At 21° C., ¼ ofthe methyl acrylate solution was added, then ⅕ of the Triton-B solutionwas added (exothermic reaction: the temperature climbed immediately to38° C.). After cooling to 20° C. over 15 min, another ¼ of the methylacrylate solution was added, followed 10 min later by ⅕ of the Triton-Bsolution (immediate temperature rise to 34° C.). The mixture was thencooled to 20° C. over 15 min. After 10 min., another ¼ of the methylacrylate solution was added, followed 10 min. later by ⅕ of the Triton-Bsolution (temperature rise to 25° C.). The mixture was then cooled to20° C. over 10 min. After 10 min., the remainder of the methyl acrylatewas added, followed 10 min. later by another ⅕ of the Triton-B solution,with the remainder of the Triton-B added 5 min. after that. The reactionmixture was stirred for 1.5 h at 23° C. The brown solution wasconcentrated. The residue was partitioned between 430 gmethylcyclohexane and 56 g water at 80° C. The organic phase was washedat the same temperature with 56 g water and then concentrated. Theresidue (clear brown solution) was cooled to 0° C. while being stirredand stirred for 1 h at 0° C. The product was vacuum filtered and washedtwice with a little cold methylcyclohexane, then dried. 111.2 gcrystalline CMD were obtained. Yield: 87.2% relative to(3-cyclopentyloxy-3-methoxyphenyl)acetonitrile

EXAMPLE 5 Production of CMOM

33.98 g (82 mmol) CMD (97%) were dissolved in 90 g dioxane and mixed atroom temperature with 18.75 g (104 mmol) 30% sodium methoxide. Thesolution was heated to reflux temperature over 20 min. After 30 min.,practically all of the educt was converted (as confirmed by thin-layerchromatography) and one began to draw off the distillate. A total of26.4 g distillate were removed in 90 min. The solution was cooled to 60°C., resulting in an easily stirred, beige suspension. 10.03 g (119 mmol)sodium bicarbonate and 100 g water were added to the suspension,yielding a mixture with two almost clear phases. This was taken directlyinto the next stage.

EXAMPLE 6 Production of CMC

Approximately 253 g reaction mixture from the previous stage were heatedto reflux. This was stirred for a total of 10 h with a bath temperatureof 110° C. and an internal temperature of 87° C. Thin-layerchromatography confirmed that the conversion was complete at this time.A total of 104 g distillate were drawn off from this 2-phase mixture. Amixture of 124 g (161 ml) methylcyclohexane and 14 g (16 ml) ethylacetate was added to the easily stirred suspension after it had beencooled to 85-90° C. At a reactor temperature of 90° C. and with slowreflux, the clear water phase was drained off and the yellow organicphase was washed at the same temperature with 80 g water (in twoportions). The organic phase was cooled to 0° C. over 1 h. After 1 h at0° C., this phase was filtered, the residue washed with 80 mlmethylcyclohexane/ethyl acetate 9:1 (w/w, cold) in two portions, anddried (approximately 4 h, 20 mbar, 55° C.). 17.91 g crystallized productwere obtained with a content of 98.9% (HPLC). The mother liquor wasevaporated and dried, yielding 2.99 g product with a CMC content of62.7%. Yield: 17.91 g product with a content of 98.9% was equivalent to56.5 mmol=69% yield relative to initial quantity of CMD (i.e. over bothstages). The total yield of CMC thus formed was 77%.

SUMMARY

A new process is described for production of1-(3-cyclopentyloxy-4-alkoxyphenyl)-4-oxocyclohexanecarbonitrile of thegeneral formula

In this process, a4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-heptanediacid dialkyl esterof the general formula

is cyclized in the presence of a base to a5-cyano-5-(3-cyclopentyloxy-4-alkoxyphenyl)-2-oxocyclohexanecarboxylicacid alkyl ester of the general formula

then the compound of the general formula III is neutralized with analkali metal hydrogen carbonate and this product is then decarboxylatedin the presence of an alkali metal carbonate to form the end product asper formula I.

What is claimed is:
 1. Process for production of a1-(3-cyclopentyloxy-4-alkoxyphenyl)-4-oxocyclohexanecarbonitrile of thegeneral formula

wherein R¹ signifies a C₁₋₅-alkyl group, comprising the cyclization of a4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)heptanediacid dialkyl esterof the general formula

wherein R¹ has the given meaning and R² and R³ signify C₁₋₅-alkylgroups, in the presence of a base, to a5-cyano-5-(3-cyclopentyloxy-4-alkoxyphenyl)-2-oxocyclohexanecarboxylicacid alkyl ester of the general formula

wherein R¹ and R² have the given meanings, neutralization of thecompound to the general formula III with an alkali metal hydrogencarbonate and then decarboxylation, in the presence of an alkali metalcarbonate, to the end product as per formula I.
 2. Process according toclaim 1, whereby one uses an alkali metal alkoxide as base for thecyclization.
 3. Process according to claim 1, whereby one conducts thedecarboxylation under weakly basic conditions.
 4. Process according toclaim 1, whereby one carries out the cyclization and the decarboxylationin a polar solvent.
 5. Process according to claim 4, whereby one uses anether as the polar solvent.
 6. Process according to claim 1, whereby the4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)heptanediacid dialkyl esterof the general formula II, wherein R¹, R² and R³ have the givenmeanings, is produced such that in a first stage, an isovanillinderivative of the general formula

wherein R¹ has the given meaning, is converted with a halogencyclopentane into a 3-cyclopentyloxy-4-alkoxybenzaldehyde of the generalformula

wherein R¹ has the given meaning, and this product is reduced in asecond stage to a (3-cyclopentyloxy-4-alkoxyphenyl)methanol of thegeneral formula

wherein R¹ has the given meaning, and this product is halogenated in athird stage to a 4-(halogenmethyl-2-cyclopentyloxy-1-alkoxy)benzene ofthe general formula

wherein R¹ has the given meaning and X signifies a halogen atom, andthis product is then converted in a fourth stage into a(3-cyclopentyloxy-4-alkoxyphenyl)acetonitrile of the general formula

wherein R¹ has the given meaning, and finally this product is convertedin the fifth stage with an alkyl acrylate into4-cyano-4-(3-cyclopentyloxy-4-alkoxyphenyl)heptanediacid dialkyl esterof the general formula II.